The compounds of the invention are variously functionalized, with a view to varying lipid solubility, size, function and other properties, with the particular aim of the discovery of novel drug or drug-like compounds, or compounds with useful properties. The invention provides intermediates, processes and synthetic strategies for the solution or solid phase synthesis of various amides of a-and P-D-glucosamine and-galactosamine, their PEG- glycosides and other glycosides, with various functionality about the sugar ring, including the addition of aromaticity, and the placement of amino acid and peptide units or their isosteres.

These compounds are structural mimetics of the substrates of enzymes in the muramyl pathway in peptidoglycan biosynthesis. It is expected that compounds of the type proposed, or analogues thereof, will act as inhibitors of the formation of the peptidoglycan layers that protect bacterial cell membranes or as inhibitors of other bacterial enzymes. Thus compounds of this type are attractive targets for the discovery of new antibiotics and antibacterials.

BACKGROUND OF THE INVENTION Since the discovery of penicillin in 1928 the apparent ability of the ever-growing numbers of available antibiotics to treat infections and disease has, until recently, caused a high degree of complacency about the threat of bacterial resistance. This complacency has created a situation where antibiotics are over-prescribed in both hospitals and in the community, and used

extensively in animal feeds. The alarming speed with which bacteria have become resistant to microbial agents has meant that there is a very real danger that infections, which were until recently completely controllable, will pose serious threats to human health.

All unicellular bacteria contain a cell wall which is associated with a diverse range of functions, although the major one is that of protecting the cell from lysing under high internal osmotic pressures. The cell wall is composed of peptidoglycan, a rigid mesh of ß-1, 4-linked carbohydrate polymers covalently cross-linked by peptide chains. The peptidoglycan synthetic pathway is not present in mammalian systems, suggesting that the side-effects associated with such inhibitors could be minimized. Thus the bacterial peptidoglycan biosynthetic pathway presents an opportunity for the development of novel antibacterial agents.

There is a great deal of interest in the substrates of the muramyl pathway and their analogues, and in the synthesis of related compounds that may result in new therapeutics. Tanner and co-workers have recently prepared compounds that inhibit the MurD and MurE enzymes of the muramyl pathway. These non-carbohydrate compounds have the sugar and lactate moieties of a muramic acid-like compound replaced with a five carbon linker unit (Zeng, B., Wong, K. K., Pompliano, D. L.,, Reddy, S., and Tanner, M. E., JOC 1998 63 (26) 10081-5; Tanner, M. E., Vaganay, S., van Heijenoort, J., and Blanot, D., JOC 1996 61 (5) 1756-60), and are prepared by standard organic chemistry techniques.

They are linear, flexible organic compounds with substituents that resemble those of UDP-MurNAc-pentapeptide (the"Park Nucleotide" (Park, J. J. Biol. Chem. 1952,194, 877)). One of those compounds in particular was found to be a relatively potent inhibitor of MurE (Zeng, B., Wong, K. K., Pompliano, D. L., Reddy, S., and Tanner, M. E. JOC 1998 63 (26) 10081-5).

In other studies on an analogous phosphinate inhibitor of MurD, it was found that retaining the MurNAc

sugar residue, instead of replacing it with a carbon linker unit, increases the potency of the inhibitor by almost two orders of magnitude (Gegnas, L. D., Waddell, S. T., Chabin, R. M., Reddy, S., Wong, K. K., Bioorg. Med. Chem. Lett.

1998 8 1643). This suggests that building a library of monosaccharide analogues of the substrates of the muramyl pathway is an attractive proposition for the generation of new therapeutics which target that system.

One approach to the synthesis of such compounds is to make use of biosynthetic techniques, such as that used in preparing labelled versions or analogues of MurNAc from GlcNAc by implementing the MurA and MurB enzymes themselves (Lees, W. J., Benson, T. E., Hogle, J. M., and. Walsh.

C. T., Biochemistry 1996,35 (5), 1342-1351).

Chemical methods require protected building blocks, and some well-established chemistry has been implemented, using GlcNAc to yield the benzyl glycoside of N-acetyl-4,6- benzylidenemuramic acid (Jeanloz, R. W., Walker, E., SinaY, P., Carbohydr. Res. 1968,6,184). One challenge to the synthesis of such compounds is the alkylation of the C-3 position of the carbohydrate residue. In the natural muramyl system, the MurA and MurB enzymes add what is ultimately a lactate moiety to the C-3 position.

The addition of a lactate moiety at C-3 has been achieved chemically in a process in which the required materials were generated through the intermediate preparation of a nitroalkene sugar (Vega-Perez, et al.

Tetrahedron 1999,55,9641-9650). An alternative approach is the alkylation of the C-3 hydroxyl with the a-bromide of an appropriately protected propianoic acid to generate the required compound (Iglesias-Guerra, F., Candela, J. I., Bautista, J., Alcudia, F., and Vega-Perez, J. M., Carb. Res.

1999,316,71-84).

Having compounds with a lactate moiety, or similar acid, in place at C-3 allowed the addition of amino acids to build the required pentapeptide substituent. This molecule was subsequently converted to the natural

substrates for the muramyl enzyme system (Hitchcock, C. N., Eid, J. A., Aikins, M. Z-E., and Blaszczak, L. C., J. Am.

Chem. Soc. 1998,120 (8), 1916). In a similar approach the preformed pentapeptide was added as a single unit to yield muramyl products (Ha, S., Chang, E., Lo, M-C., Men, H., Park, P., Ge, M., and Walker, S., J. Am. Chem. Soc. 1999, 121 (37), 8415).

Combinatorial chemistry and parallel synthesis have become the methods of choice for the rapid synthesis of a large number of related compounds simultaneously, and this approach has been used to produce libraries of compounds to be screened for biological activity. Sometimes such libraries are focussed to test for activity of the compounds so generated towards a particular biological agent or organism, although often large libraries are also prepared in a random fashion. Either way, the intended end result of combinatorial chemistry is the rapid discovery and optimization of leads for the development of new pharmaceuticals.

Despite the obvious advantages of a combinatorial approach to the preparation of compounds for drug discovery, this technique is underexplored in the field of carbohydrate chemistry. This is primarily because of the well-known difficulties associated with the synthesis of carbohydrate compounds. For that reason carbohydrate libraries prepared in the past have tended to be relatively simple. For example, Hindsgaul et al have produced a library of monosaccharide compounds by a combinatorial approach (Ole Hindsgaul US Patent 5780603); however, the variation in the compounds was limited to the glycosidic bond. A glycopeptide library in which mannose residues were decorated with various amino acids has been described, but these were conjugated to the sugar solely through the C-6 position (Tennant-Eyles, R. J., and Fairbanks, A. J., Tetrahedron Asymmetry. 1999,10,391-401).

Access to greater variation has been attempted by making used of libraries of carbohydrate mimetics

(Byrgesen, E., Nielsen, J., Willert, M., and Bols, M., Tetrahedron Lett. 1997,38,5697-5700 and Lohse, A., Jensen, K. B., and Bols, M., Tetrahedron Lett., 1999,40, 3033-3036). However, one approach which successfully added greater diversity to monosaccharides was that of Goebel and Ugi (Tetrahedron Lett., 1995,36 (34), 6043-6046) who generated a small library of alkylated glycals by subjecting protected glucals to electrophilic attack and then subsequent reactions. Unfortunately this method is limited by the fact that each starting glucal may give rise to a number of isomeric products.

For these reasons there is particular interest in libraries of aminoglycosides and amino sugars for drug discovery. Some work on such compounds has been published, with Silva and co-workers preparing impressive disaccharide libraries containing glucosamine (Silva, D. J., Wang, H., Allanson, N. M., Jain, R. K., and Sofia, M. J., JOC 1999, 64 (16), 5926-5929). However, this library still suffers from the limitation that the variation is limited solely to acylations of the amino group.

More variation, and in fact a three-dimensional diversity, was obtained in the preparation of amino sugars by Sofia and co-workers (Sofia, M. J., Hunter, R., Chan, T. Y., Vaughan, A., Dulina, R., Wang, H., and Gange, D., JOC 1998,63 (9), 2802-2803). This allowed chemical diversity at three combinatorial sites on the sugar residue. Other workers have prepared a library of compounds with four (Wunberg, T., Kallus, C., Opatz, T., Henke, S., Schmidt, W., and Kunz, H., Angew. Chem. Int. Ed.

1998,37 (18), 2503-2505), and five (Kallus, C., Opatz, T., Wunberg, T., Schmidt, W., Henke, S., and Kunz, H., Tetrahedron Lett. 1999,40,7783-7786) such sites of functionalization, although these compounds were not amino- sugars.

It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of

these documents forms part of the common general knowledge in the art, in Australia or in any other country.

Hitherto, there have been few attempts to synthesise analogues of the muramyl substrates, particularly those which contain modifications at the anomeric position or at the C-2 nitrogen. The natural substrate and all of the muramyl enzyme intermediates contain exclusively the a- glycosidic diphosphate. Our modelling and design studies with the crystal structure of the Mur D enzyme suggest that both the a or P anomeric configuration of many of the compounds proposed in this invention can fit into the active site of this enzyme. We believe that this is the first time that a-glycosides which contain no phosphate groups have been prepared as potential inhibitors of the muramyl enzyme system.

Many of the traditional methods of carbohydrate synthesis have proved to be unsuitable to a combinatorial approach, particularly because modern high-throughput synthetic systems require that procedures to be readily automatable. The compounds and processes described herein are particularly suited to the solid and solution phase combinatorial synthesis of carbohydrate-based libraries, and are amenable to automation. The methods of the invention yield common intermediates which are suitably functionalized to provide diversity in the structure of the compounds so generated. In this way the technology described can produce many and varied compounds around the basic structure shown in formula I. Using this method, it is possible to introduce varied functionality in order to modulate both the biological activity and pharmacological properties of the compounds generated.

Thus the compounds and methods disclosed herein provide the ability to produce random or focussed combinatorial-type libraries not only for the discovery of new antibacterial agents, but also for the discovery of other novel drug or drug-like compounds, or compounds with other useful properties.

SUMMARY OF THE INVENTION According to the present invention there is provided a monosaccharide compound of general formula I in which the monosaccharide ring is of the glucosamine or galactosamine configuration; R4 and Rs are hydrogen or together form an optionally substituted benzylidene acetal in which the optional substituent is chosen from halo, azido, alkoxy, nitro or alkyl ; R3 is hydrogen; optionally substituted glycolate or optionally substituted lactate or derivatives thereof; or a carboxylic acid mimetic; R1 is optionally substituted acyl, optionally substituted benzoyl, optionally substituted biphenylcarbonyl, heteroaryl acyl, optionally substituted bicycloacyl, optionally substituted bicycloheteroacyl, sulfonamide, urea or carbamates; R2'is hydrogen; R1 and R2'together form succinimide, maleimide or optionally substituted phthalimide, R is N3, O-Y, in which Y is

in which Z is positioned on one or both of the aromatic rings of the bicyclic structures and is independently selected from OH, SH, CF3, alkyl, alkenyl, alkynyl, NO2, halo, SO3H, NH2, CO2H, azido, nitroso, alkoxy, aryloxy, SO2NH2, amidine and guanidinium; q is 0 or 1; m is an integer of 0 to 3; Z'is halo, optionally substituted S-aryl, optionally substituted S-heteroaryl, optionally substituted aryl or optionally substituted heteroaryl; Zizis an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl ; X is O, NH or S;

Y'is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroaryl alkyl, in which Z'''is O, NH or S ; R6 is H, CONH2 or COOH ; n is an integer of 0 to 4 ; R7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl R8 is H, OH, NH2, alkyl, alkenyl or alkynyl; Rg is H, OH, NH2, or NHCO-Rlo in which Rlo is an optionally substituted alkyl ; Rll is an optionally substituted alkylene, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl; and Y''is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heteroaryl alkyl,

derivatives thereof, tautomers thereof and/or isomers thereof.

The term"derivatives"is used herein in its broadest sense to include protected forms and synthetic precursors of compounds of the present invention, for example, azide is a protected form/precursor of amine, nitrile is a protected form/precursor of amine, carboxylic acid and amide.

The term"tautomer"is used herein in its broadest sense to include compounds of formula I which are capable of existing in a state of equilibrium between two isomeric forms. Such compounds may differ in the bond connecting two atoms or groups and the position of these atoms or groups in the compound.

The term"isomer"is used herein in its broadest sense and includes structural, geometric and stereo isomers. As the compound of formula I may have one or more chiral centres, its is capable of existing in enantiomeric forms. The anomeric centre of the monosaccharide ring may also be of either the a or P configuration.

The term"halo"denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

The term"alkyl"used either alone or in compound words such as"optionally substituted alkyl","optionally substituted cycloalkyl","arylalkyl"or"heteroarylalkyl", denotes straight chain, branched or cyclic alkyl, preferably Cl6alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1, 1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3- methylpentyl, 1, 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl, 1, 2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2- trimethylpropyl, 1, 1,2-trimethylpropyl, heptyl, 5- methylbexyl, 1-methylhexyl, 2,2-dimethypentyl, 3,3-

dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3- trimethylbutyl, 1, 1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3- tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6-or 7- methyloctyl, 1-, 2-, 3-, 4-or 5-ethylheptyl, 1-, 2-or 3- propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8- methylnonyl, 1-, 2-, 3-, 4-, 5-or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-ethylnonyl, 1-, 2-, 3-, 4-or 5-propyloctyl, 1-, 2-or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8- ethyldecyl, 1-, 2-, 3-, 4-, 5-or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2 pentylheptyl and the like. Examples of cyclic alkyl include mono-or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.

The term"alkylene"used either alone or in compound words such as"optionally substituted alkylene" denotes the same groups as"alkyl"defined above except that an additional hydrogen has been removed to form a divalent radical. It will be understood that the optional substituent may be attached to or form part of the alkylene chain.

The term"alkenyl"used either alone or in compound words such as"optionally substituted alkenyl" denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di-or poly- unsaturated alkyl or cycloalkyl groups as defined above, preferably C26alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2- butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-

cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3- cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl.

The term"alkynyl"used either alone or in compound words, such as"optionally substituted alkynyl" denotes groups formed from straight chain, branched, or mono-or poly-or cyclic alkynes, preferably C26 alkynyl.

Examples of alkynyl include ethynyl, 1-propynyl, 1-and 2- butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, 2-hexynyl, 3-hexylnyl, 4-hexynyl, 5-hexynyl, 10- undecynyl, 4-ethyl-l-octyn-3-yl, 7-dodecynyl, 9-dodecynyl, 10-dodecynyl, 3-methyl-1-dodecyn-3-yl, 2-tridecynyl, 11- tridecynyl, 3-tetradecynyl, 7-hexadecynyl, 3-octadecynyl and the like.

The term"alkoxy"used either alone or in compound words such as"optionally substituted alkoxy" denotes straight chain or branched alkoxy, preferably Cl7alkoxy. Examples of alkoxy include methoxy, ethoxy, n- propyloxy, isopropyloxy and the different butoxy isomers.

The term"aryloxy"used either alone or in compound words such as"optionally substituted aryloxy" denotes aromatic, heteroaromatic, arylalkoxy or heteroaryl alkoxy, preferably C6-13 aryloxy. Examples of aryloxy include phenoxy, benzyloxy, 1-napthyloxy, and 2-napthyloxy.

The term"acyl"used either alone or in compound words such as"optionally substituted acyl"or "heteroarylacyl"denotes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl. Examples of acyl include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-

butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e. g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e. g. naphthylacetyl, naphthlpropanoyl and naphthylbutanoyl); aralkenoyl such as phenylalkenoyl (e. g. phenylpropenoyl, phenylbutenoyl, phenylmethacrylyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e. g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e. g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and naphthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and naphthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienyglyoxyloyl.

The term"aryl"used either alone or in compound words such as"optionally substituted aryl","arylalkyl"or "heteroaryl"denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, phenoxyphenyl,

naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4-phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, pyrrolyl, furanyl, imadazolyl, pyrrolydinyl, pyridinyl, piperidinyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like. Preferably, the aromatic heterocyclic ring system contains 1 to 4 heteroatoms independently selected from N, O and S and containing up to 9 carbon atoms in the ring.

The term"heterocycle"used either alone or in compound words as"optionally substituted heterocycle" denotes monocyclic or polycyclic heterocyclyl groups containing at least one heteroatom atom selected from nitrogen, sulphur and oxygen. Suitable heterocyclyl groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated to 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidin or piperazinyl ; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolizinyl, benzimidazoyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, such as, pyranyl or furyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoxazolyl or oxadiazolyl;

saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl or thiadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl.

In this specification"optionally substituted" means that a group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, carboxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, nitroso, azido, amidine, guanidium, amino, alkylamino, alkenylamino, alkynylamino, arylamino, benzylamino, acylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, acyloxy, aldehydo, alkylsulphonyl, arylsulphonyl, sulphonylamino, alkylsulphonylamino, arylsulphonylamino, alkylsulphonyloxy, arylsulphonyloxy, heterocyclyl, heterocycloxy, heterocyclylamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy, mercapto, sulfonic acid, alkylthio, arylthio, acylthio and peptidomimetics.

Preferred optional substituents include OH, SH, CF3, alkyl, alkenyl, alkynyl, NO2, halo, S03H, NH2, C02H, azido, nitroso, alkoxy, aryloxy, S02NH2, amidine, guandinium or peptidomimetics.

A preferred compound of formula I has the formula Ia

in which the monosaccharide ring is of the glucosamine or galactosamine configuration and the anomeric centre may be either the a or ß configuration; R5, R4 and R3 are as defined in formula I above; R2 is hydrogen; Ri is (i) C2-8 acyl which may be branched or linear and optionally substituted with one or more OH, SH, CF3, NO2, halo, SO3H, NH2, CO2H, azido, nitroso, alkoxy, aryloxy, SO2NH2, amidine or guanidinium; (ii) a benzoyl group which may be optionally substituted with one or more OH, SH, CF3, alkyl, alkenyl, alkynyl, NO2, halo, SO3H, NH2, CO2H, azido, nitroso, alkoxy, SO2NH2, amidine or guanidinium; (iii) a biphenylcarbonyl group which may be optionally substituted on either one or both of the aromatic rings with one or more of OH, SH, CF3, alkyl, alkenyl, alkynyl, NO2, halo, SO3H, NH2, CO2H, azido, nitroso, alkoxy, SO2NH2, amidine or guanidinium; or (iv) a heteroaryl acyl, sulfonamide, urea or carbamate; R1 and R2 together form optionally substituted succinimide, optionally substituted maleimide or optionally substituted phthalimide; Y is as defined in formula I above in which the optional substituents for Z'or Z''are at least one of OH, SH, CF3, alkyl, alkenyl, alkynyl, NO2, halo, S03H, NH2,

COzH, azido, nitroso, alkoxy, aryloxy, SO2NH2, amidine or guanidinium.

Preferably, the glycolate or lactate or derivatives thereof are optionally substituted with at least one amino acid or peptidomimetic.

Examples of suitable peptidomimetic substiuents which may be used at R3 are disclosed in Gante, J., Angew. Chem.

Int. Ed. Engl., 1994,33,1699-1720 and Giannis, A., and Kolter, T., Angew. Chem. Int. Ed. Engl., 1993,32,1244- 1267).

Non-limiting examples of carboxylic acid mimetics and other suitable substituents for R3 are: NA' F x p O B NFrpeptide B71\1 BA- S03H SOZNHU O 0 N O N O HN. N in which A and B are independently hydrogen, alkyl, trihaloalkyl or halo; A'is hydrogen or alkyl ; A''is hydroxy, optionally substituted amine or oxyaryl; U is hydrogen, aryl, heteroaryl, alkyl, alkenyl or alkynyl each of which may be optionally substituted with one or more of OH, SH, CF3, alkyl, alkenyl, alkynyl, N02, halo, S03H, NH2, CO2H, azido, nitroso, alkoxy, SO2NH2, amidine or guanidinium; and

W is hydrogen or an acidic or acid mimetic, such as, for example, OH, SH, CF3, NO2, halo, SO3H, CO2H, azido, nitroso, alkoxy, aryloxy, SO2NH2, or forms a carbocyclic or heterocyclic ring.

Another preferred compound of formula I has the formula Ib in which the monosaccharide ring substitution is of the glucosamine or galactosamine configuration and the anomeric centre may be of the a or ß configuration; R5, R4 and R3 are as defined in formula I above; R2 and R1 are as defined in formula Ia above; Rl'is N2 or in which X is 0, NH or S; and Y'is as defined in formula I above in which R7 may be optionally substituted with at least one of OH, SH, CF3, alkyl, alkenyl, alkynyl, NO2, halo, SO3H, NH2, CO2H, azido, nitroso, alkoxy, SO2NH2, amidine or guanidinium.

A further preferred compound of formula I has the formula Ic

in which the monosaccharide ring substitution is of the glucosamine or galactosamine configuration and the anomeric center may be of the a or ß configuration; in which R5, R4 and R3 are as defined in formula I above; Rz and R1 are as defined in formula Ia above; Y''is as defined in formula I above and may be optionally substituted with one or more OH, SH, CF3, alkyl, alkenyl, alkynyl, NO2, halo, S03H, NH2, CO2H, azido, nitroso, alkoxy, SO2NH2, amidine or guanidinium.

The present invention also provides a method for the preparation of a compound of general formula I, comprising the step of glycosylating an intermediate compound of formula IV, in which L is a leaving group and L'is a protecting groups with an alcohol or phenol acceptor.

The leaving group may be of any suitable known type, such as, for example, those leaving groups disclosed in J.

March,"Advanced Organic Chemistry: Reactions, Mechanisms and Structure"4th Edition, pp 352-357, John Wily & Sons, New York, 1992 which is incorporated herein by reference.

Preferably, the leaving group is acetate, thiomethyl, trichloroacetimidyl or halogen, more preferably bromine or chlorine.

Suitable protecting groups include those disclosed in Greene, T. W.,"Protective Groups in Organic Synthesis", John Wiley & Sons, New York, 1981, such as optionally substituted silyl, optionally substituted alkyl, optionally substituted acyl or optionally substituted heteroacyl, for

example, azide or 4,4-dimethyl-2,6-dioxocyclohex-1-y-idene (Dde), tbutyldimethylsilyl, tbutyldiphenylsilyl, benzylidene, 4-methoxybenzylidene, benzoate, acetate, chloroacetate, 9-fluorenylmethylcarbamate, benzyloxy carbamates, isopropylidene and 4-methoxyphenyl.

Examples of suitable alcohols include methanol, ethanol, propanol, iso-propanol, benzyl alcohol, 2', 2- chloroethoxyethanol, 2'', 2', 2-chloroethoxyethoxyethanol, 2- napthylmethanol, 1-napthylmethanol, allyl alcohol, 5- penteneol, 4-buteneol, butanol, sec-butanol and n-butanol.

Examples of suitable"phenol acceptor"include 4- nitrophenol, phenol, resorcinol, phloroglucinol, 4- chlorophenol, catechol and 4-allylphenol.

The present invention further provides a method for the preparation of a compound of formula I, in particular formula Ib or Ic, comprising the step of acylating an intermediate compound of general formula V in which L''is hydrogen, NO2, halo, azido or alkoxy.

The compounds of the present invention are useful in screening for biological activity, particularly use of compounds of the formulae Ia, Ib and Ic for screening for anti-bacterial or antibiotic activity. In particular,

compounds of the invention are useful in screening for inhibitory activity against one or more enzymes of the muramyl cascade.

Thus, according to a further aspect of the present invention there is provided a method of screening for antibacterial or antibiotic compounds comprising the steps of: (a) forming a combinatorial library comprising a compound of the formula I defined above; and (b) testing the combinatorial library for antibacterial or antibiotic activity.

According to a still further aspect of the present invention there is provided an antibacterial or antibiotic compound identified using the method defined above.

In a particularly preferred embodiment for this purpose, the compound of formula Ia has structure A Structure A in which R5'and R4'are hydrogen or together form a benzylidene-type acetal; R3'is a lactate or lactate mimetic which may be optionally substituted with short peptides or peptidomimetics such as those found in the muramyl enzyme products; R1'is an acetyl group as in the naturally-occurring system; or NHCOR1'may be other amides, sulfonamides, urea and the like; and YA is a structural or functional mimetic of uridine diphosphate or a simple diphosphate.

Analogous compounds to Structure A of the formulae Ib and Ic of the invention are also contemplated as preferred embodiments for this purpose.

For the purposes of this specification it will be clearly understood that the word"comprising"means "including but not limited to", and that the word "comprises"has a corresponding meaning.

BRIEF DESCRIPTION OF THE FIGURES Figures 1 to 3 show HPLC and mass spectra for representative compounds produced following General Step 9.

Figure 1 : 1- [2'- (2''- (4'''-chlorophenylthio) ethoxy) ethyl]- 2-deoxy-2-benzoylamino-ß-D-glucose. HPLC and mass spectrum.

Figure 2: l-[2'-(2''-(2'''-(m-trifluoromethylphenylthio) ethoxy) ethoxy) ethyl]-2-deoxy-2-acetylamino-ß-D-glucose.

HPLC and mass spectrum.

Figure 3: 1-[2'-(2''-(2'''-(m, p-dichlorophenylthio) ethoxy) ethoxy) ethyl]-2-deoxy-2- (3', 3', 3'trimethylpropionylamino)-p-D-glucose. HPLC and mass spectrum.

Figure 4a shows a lHnmr spectrum and Figure 4b shows a mass spectrum for a protected tripeptide product produced according to General step 10. 1- [21- (2''- (2111- chloroethoxy) ethoxy) ethyl]-2-deoxy-2-benzoylamino-4,6-0- <BR> <BR> <BR> benzylidene-3-0-methylcarbonyl-[((a-0-benzyl)-Y-glutamyl)-&l t;BR> <BR> <BR> <BR> <BR> (N6- (2'chlorobenzylcarbamoyl)-lysinyl)- (O-benzylalanyl)]-P- D-glucopyranoside.

DETAILED DESCRIPTION OF THE INVENTION The invention will now be described in detail by way of reference only to the following non-limiting examples and to the drawings.

Abbreviations used herein are as follows: AN Acetonitrile MeCN Acetonitrile

Ether Diethyl Ether DCM methylene chloride; dichloromethane MeOH methanol EtOAc Ethyl Acetate DMF N, N-dimethylformamide HBTU O-benzotriaxol-l-yl-N, N, N', N'- tetramethyuronium hexafluorophosphate TBAF tetrabutylammonium fluoride Dde 4,4-dimethyl-2,6-dioxocyclohex-l-ylidene BOP Benzotriazol-1-yloxy- tris (dimethylamino) phosphonium hexafluorophosphate PyBOP Benzotriazol-l-yloxy-tris (pyrollidyl) phosphonium hexafluorophosphate HATU 0- (7-Azabenzotriaxol-l-yl)-N, N, N', N'- tetramethyuronium hexafluorophosphate Fmoc 9-Fluorenylmethylcarbamate Boc t-Butylcarbamate Experimental Support Exemplary compounds of the invention were prepared as set out in the following synthetic schemes 1 to 3 and detailed in the general procedures.

All final compounds were purified by liquid chromatography-mass spectrometry (LC-MS), using a micromass LCZ electrospray mass spectrometer as detector. Proton NMR results are included for representative compounds. 0 HO Ac0 H NH3a H Ac NHDJE OH OH OAc OH 0 i D-Glucosamine hydrochloride Ace A A General Step 1 e 0 Ac e OAc OAc General Step 2 4 3 O O-Y O O-Y General Step 3 p HoYNHMe y\NHDde OH \ I OH 5 OH General Step 4 0 0-Y 0 0-Y 0 0 8 (x OH 7 (Xo H 9 80t OH sy 70 OH General Step 5 0 0-Y 0 0-Y O O 8 (3 o"' 7p OH \ g OH \, 7 OH

Scheme 1 y = benzyl, napthylmethyl, 2'-chloroethoxyethyl, 2'' chloroethoxyethoxyethyl.

Ri = methyl, phenyl, tbutyl, tbutylmethylene, biphenyl.

2-deoxy-2- [1- (4, 4-dimethyl-2, 6-dioxocyclohex-1-ylidene)-<BR> <BR> <BR> <BR> <BR> <BR> <BR> ethylamino-a-D-glucopyranose (1) Glucosamine hydrochloride (50g, 231mmol) was suspended in anhydrous methanol (500ml), then 2-acetyl-dimedone sodium salt (47.3g, 231mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes, then 2-acetyl- dimedone (21.1g, 115.9mmol) was added. The reaction mixture was stirred under reflux for 2.5 hours and monitored by tlc. At the completion of the reaction (TLC: MeCN-H20, 10: 2), the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the resulting solid residue was washed on a funnel with ether (3 x 500 ml) and dried to give crude product (75g, 94%). No further purification was required for the next reaction. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>1, 2, 4, 6-tetra-0-Acetyl-2-deoxy-2- [2- (4, 4-dimethyl-2, 6-<BR> <BR> <BR> <BR> <BR> <BR> dioxocyclohex-1-ylidene)-ethylaminol-a-D-glucopyranose (2) Crude 2-Deoxy-2- [l- (4, 4-dimethyl-2,6-dioxocyclohex-1- ylidene)-ethylamino]-a,-D-glucopyranose (75g, 218.6mmol) was dissolved in pyridine (320ml) and acetic anhydride (165ml) was added dropwise keeping the temperature below 30°C. The reaction mixture was stirred overnight then solvents evaporated. Toluene (2 x 100ml) was evaporated off the residue. The residue was taken up in CH2C12 (550ml), washed with 5% HC1 solution (280ml), water (3 x 11), saturated NaHCO3 (11), then dried over magnesium sulphate and the solvents evaporated. The product was crystallised from MeOH (250ml), filtered, washed with cold MeOH (-40°C) on the funnel. The solid was dried to give 1,2,4,6-tetra-O- Acetyl-2-deoxy-2-Deoxy-2- [l- (4, 4-dimethyl-2,6- dioxocyclohex-l-ylidene)-ethylamino]-a-D-glucopyranose (95g, 85%).

3,4,6-tri-O-Acetyl-2-deoxy-2-f1- (4, 4-dimethyl-2, 6- dioxocyclohex-1-ylidene)-ethylamino]-a-D-glucopyranosyl bromide (3) 1, 2,4,6-tetra-0-Acetyl-2-deoxy-2- [l- (4,4-dimethyl-2,6- dioxocyclohex-1-ylidene)-ethylamino]-oc-D-glucopyranose (150g, 293.5 mmol) was dissolved in dry CH2C12 (300 ml) and hydrogen bromide in acetic acid (400 ml, 30%) was added.

The reaction mixture was stirred at room temperature for 2 hours, then diluted with cold CH2C12 (-15°C, 2 1) and washed with cold water (0°C, 3 times 21), saturated NaHCO3 (2 1).

The organic phase was dried over MgS04 and evaporated in vacuo at 30°C. The resulting white solid residue was suspended in ether (1 1) and filtered. The solid was dried under vacuum giving 3,4,6-0-acetyl-2-deoxy-2- [l- (4,4- dimethyl-2, 6-dioxocyclohexa-l-ylidene)-ethylamino]-o-D- glucopyranosyl bromide (150g, 95%).

Rf 0.62 (EtOAc/Hexane 2: 1); MS (electrospray) C22H3oBrNO9 (532.1/534.0) m/z (%) 533.38/535.38 [M + H] + (100).

General Step 1 : Reaction of (3) with acceptor alcohols A mixture of 3,4,6-tri-O-acetyl-2-deoxy-2- [l- (4,4-dimethyl- 2,6-dioXocyclohex-1-ylidene)-ethylamino]-X-D-glucopyranosyl bromide (3) (1 equivalent), the acceptor alcohol (1.5 equivalents) and activated [4A] molecular sieves (equal mass as bromide (3)) were stirred in 1,2-dichloroethane (10 ml per gram of (3)) under a nitrogen atmosphere at-78°C in a flask that had been covered to preclude ambient light.

Silver triflate (1.45 equivalents) was added and the mixture allowed to warm to room temperature. This reaction was then stirred at room temperature for 1 hour, diluted with CH2C12 (20 mL per gram of (3)) and filtered through a plug of Celite. The eluent was then washed with saturated NaHCO3 (3 times 10 ml per gram of (3)), dried (MgS04) and the solvent removed in vacuo to yield an anomeric mixture of the glycosylated compounds.

Acceptor A = 2- (2- (2-Chloroethoxy) ethoxy) ethanol, amount of (3) used 21 gm, yield 4A 20.57 gm (84%) MS (electrospray) C28H42ClNOl2 (619.3/621.2) m/z (%) 620.32/622.4 [M + H] + (100).

Acceptor B = 2- (2-Chloroethoxy) ethanol, amount of (3) used = 35 gm, yield 4B 37 gm 97% Acceptor C = 2-napthylmethanol, amount of (3) used 34.5 gm, yield 4C 25.75 gm (66%) MS (electrospray) C33H39NOlo (609) m/z (%) 610 [M + H] + (100).

Acceptor D = Benzyl alcohol Amount of (3) used 2.24 gm, yield 4D 2.35 gm General Step 2 : Deacylation of glycosylation products 4 Products of general step 1 (1 eq) were dissolved in methanol (4 ml per gram of substrate) and sodium metal (10 mg per gram of substrate dissolved in methanol) was added.

The reaction vessel was fitted with a calcium chloride guard tube and the mixture stirred at room temperature for 30 minutes with monitoring by t. l. c (EtOAc/Hexane 2: 1).

When the reaction was complete Amberlite IR-120 (H) cation exchange resin was added to the mixture until slightly acidic (pH 5-6). The resin was filtered off and the solvent removed in vacuo. The residue was further purified by passing through a short column of silica gel and eluting with (acetonitrile/water 10: 1). Solvents were removed to yield the desired triols 5A, 5B, and 5C 5A) Substrate 41.30 grams yield 30.98 grams (94%) MS (electrospray) C22H36ClNOg (493.2,495.1) m/z (%) 494,496 [M + H] + (30); (516. 1,518.2) m/z (%) 516,518 [M + Na] + (100).

5B) amount of substrate 4B 37 gm, Yield 28.5 gm 97%

5C) amount of substrate 4C 25.70 gm, Yield 18.24 gm (89%) MS (electrospray) C27H33NO7 (483) m/z (%) 484 [M + H] + (100) ; (507) m/z (%) 507 [M + Na] + (35).

General Step 3 : Benzylidene acetal formation Product from general step 2 (5A, 5B or 5C) 1 equivalent was dissolved in dry acetonitrile (7.5 mL per gram of substrate), benzaldehyde dimethyl acetal (2 equivalents) and para-toluenesulfonic acid monohydrate (2 mg per gram of substrate) were added. The flask was fitted with a calcium chloride guard tube and the mixture stirred at 60°C for 14 hours, after which triethylamine (1 ml) was added and the solvent removed in vacuo. The residue was taken into CH2C12 (20 ml per gram of substrate) and washed with brine (3 times 5 ml per gram of substrate), dried (MgS04) and the residue triturated with ether/petrol. The solvent was then removed in vacuo to yield the desired acetals as a white solid. The product was used without further purification in the next step.

General Step 4 : Removal of Dde The product of general step 3 (6A to 6C) was dissolved in a mixture of methanol and aqueous ammonia (28%) 1: 1 (20 ml per gram of substrate) and warmed to 60°C for 14 hours. The solvents were removed in vacuo and the residue purified by column chromatography (gradient acetonitrile to acetonitrile methanol 1: 1) to yield both the a and anomers as pure components. amount of substrate Crude 5A 76.5 gm, Yield 7Aa 20.6gm (38%) yields are over 3 steps.

MS (electrospray) Cl9H28ClNO (417,419) m/z (%) 418,420 [M +H] + (100), 250 (70).

Yield 7AD 12. 6 gm (23%) MS (electrospray) C19H28ClNO (417,419) m/z (%) 418,420 [M +H] + (100). amount of substrate pure 5B 34.1 gm, Yield 7Bα8.16 gm 34% Yield 7Bß 14.86 gm 62% amount of substrate crude 5C 20.30 gm, Yield 7Cal. 2gm yields are over 3 steps.

1H NMR (500 MHz, CD30D) 8 7.30-8.10 (14H m aromatics + NH2), 5.55 (1H s Ph- [CH)], ?? 5.20 (1H d J=12 napthyl CHa), 5.00 (1H d J=12 napthyl CHb), 4.95 (1H d J=4 H-1), 4.25 (1H dd J=5,10 H-4), 3.90-4.00 (1H m H-5), 3.75-3.80 (2H m H-6), 3.50 (1H t J=9.5 H-3), 2.80-2.85 (1H m H-2).

Yield 7Cß6. 58gm MS (electrospray) C24H2sNO5 (407) m/z (%) 408 [M + H]+ (100).

1H NMR (500 MHz, CD30D) 8 7.35-8.15 (14H m aromatics + NH2), 5.55 (1H s Ph-CH), 5.40 (1H d J=12 napthyl CHa), 5.05 (1H d J=12 napthyl CHb), 4.45 (1H d J=8 H-1), 4.40 (1H dd J=5,10 H-4), 3.85 (1H t J=10 H-3), 3.55-3.65 (2H m H-6), 3.45-3.5 (1H m H-5), 2.80-2.90 (1H m H-2).

General Step 5 : Selective acylation of free amine The products of general step 4 (7Aa, 7Aß, 7Ba, 7Bß, 7Ca, and 7Cß) were dissolved in dry methanol (10 ml per gram of substrate) (dry dichloromethane may be substituted for methanol) and the solution stirred at room temperature.

Where available the symmetrical anhydride of the acylating agent was added (1.05 equivelants). In the case of the biphenylcarbonyl, tButylacetyl and tButylcarbonyl acyl groups the acid chloride was used. In many cases the product began to precipitate after 5 minutes and the product was collected after 30 minutes by filtration. The solid was washed with a small amount of cold methanol. In

cases where the product did not precipitate, the product was partitioned between dichloromethane and sodium hydrogen carbonate solution. The organic layer being dried and evaporated to yield the desired product. The yields are summarized in Table 1.

Table 1 NMR data/yields for general step 5 of Scheme 1 7Aα $7Aß 7Aα 7Aß yield yield H-1 shift H-1 shift 1) Acetyl 74% 89% Not 4. 53 d recorded J=8. 0 2) Benzoyl 69% 82% 4. 95 d 4. 71 d J=4. 0 J=8. 0 3) Biphenylcarbonyl 80% 73% Not 4. 66 d recorded J=7. 0 4) tButylcarbonyl 74% 84% Not 4. 75 d recorded J=9. 0 5)tButylacetyl 68% 80% Not 4. 85 d recorded J=9. 0 7Ba 7Bß 7Bα 7Bß yield yield H-1 shift H-1 shift 1) Acetyl 44% 86% 4. 72 d 4. 77 d J=4. 0 J=8. 4 2) Benzoyl 66% 75% Not 3. 86 d recorded J=7. 7 3) Biphenylcarbonyl 87% 86% Not 3. 88 d recorded J=7. 8 4)tButylcarbonyl 85% 69% Not 4. 87 d recorded J=8. 3 5) tButylacetyl 76% 77% 4. 56 d 4. 79 d J=3.0 J=8.4 6) 2-Not 83% Not done Not nitrophenacetyl done recorded 7Ca 7Cß 7ca (3 yield yield H-1 shift H-1 shift 1) ACetyl 61% 87% 5. 10 d 4. 85 d J=3.0 J=8.0 2) Benzoyl 75% 89% Not 4. 90 d recorded J=8. 0 3) Biphenylcarbonyl 87% 82% 5. 25 d 4. 90 d J=4.0 J=8.0 4) tButylcarbonyl 58% 83% Not 4.90 d recorded J=8. 0 5) tbutylacetyl 68% 80% Not 4. 85 d recorded J=8. 2

Expected masses were observed for each compound and 1H NMR spectra were recorded for selected compounds.

General Step 6 : Alkylation of C-3 hydroxyl The products of general step 5 (8Aa, 8Aß, 8Ba, 8Bß, 8Ca, and 8Cß) with their appropriate acyl groups on nitrogen as indicated in the tables above (1 equivalent) were dried under high vacuum and added to a stirred suspension of 95% Sodium Hydride (2 equivalents) in dry N, N-dimethylformamide at 0°C under nitrogen. The mixture was stirred for 30 minutes, then the alkylating agent (methyl bromoacetate: 2 equivalents) was added and the reaction mixture allowed to warm to room temperature. The reaction was monitored by LC- MS for disappearance of starting alcohol. Typically reactions proceeded over 3 hours; however in some instances, the mixture was stirred overnight. The reaction mixture was worked up by cooling the mixture to 0°C and quenching unreacted sodium hydride with methanol. Solvents were removed in vacuo, and the residue taken up in dichloromethane and extracted with 10% citric acid, saturated sodium chloride then dried over anhydrous magnesium sulphate and concentrated.

In cognate preparations tButyl bromoacetate and benzyl bromoacetate have been used as the alkylating agent.

1H NMR spectra were recorded for 10 example products of this reaction. In each case a characteristic methyl singlet at b 3.45 was observed corresponding to the methyl ester group. The location and coupling constant of the anomeric proton remained essentially unchanged.

Exemplary yield and Mass spec data are shown in the Table 2.

Table 2 MS data/yields for general step 6 of Scheme 2 Compound Yield M+H (%) 9Cß acetate 76% 522 (100) 9Cß benzoate 66% 584 (100) 9Cß biphenylformate 82% 660 (100) 9Cß tButylformate 78% 564 (100) 9CP tButylacetate 87% 578 (100) 9Ap acetate 900 532 (50) 9AP benzoate 78% 594 (100) 9Ap biphenylformate 59% 670 (100) 9Aß tButylformate 84% 9Aß tButylacetate 77% 9BD acetate 88% 9Bß benzoate 53% 9Bß biphenylformate 81% 9B tButylformate Not recorded 9Bß tButylacetate Not recorded 9Cα acetate 77% 522 (100) 9Cα benzoate 62% 584 (100) 9Ca biphenylformate 63% 660 (100) 9Ca tButylformate 98% 564 (100) 9Cα tbutylacetate 44% 578 (100) 9Aa acetate 74% 532 (50) 9Aα benzoate 87% 594 (100) 9Aa biphenylformate 79% 670 (100) 9Aα tButylformate 9Aa tButylacetate 74% 9Bα acetate Not recorded 9Bα benzoate 93% 550 (80) 9Bα biphenylformate Not recorded 626 (100) 9Bα tButylformate 55% 530 (70) 9Ba tButylacetate 89% 544 (95) O O-Y p O", 0-Yp oov O 0 0-Y 0 8a OH General step 6 9a oco2R2 O O-Y O O-Y 0 0-Y 0 /, '. 8ß OH 9ß 0w CO2R2 w o co2Rz General step 8 General step 7 General step 9 0 °°-Yo NH kR, O O-Y-Z °' HO 9 NH X R1 lOa OCO2H l0a 13a-oY°Y-, O O-Y 13a °H ° o HO"V Y-Z NH--k R, 10 o CozH 13ß OH RH 13 (3 oH General step 8 O O-Y-Z O"0 YO Ho-"*-'k HO NH Rl eosN 9 NH R ocoZH lla 12'a General step 9 O O-Y-Z O O-Y-Z p O H O General step 9 R 2 O COZH llj CO H 126

Scheme 2 R2 = methyl, benzyl, tbutyl R1 is as defined in scheme 1 above Y is as defined in scheme 1 above Z is-S- (4-methoxy) phenyl ;-S- (4-methyl) phenyl;-S- (4-chloro) phenyl ;-S- (3, 4-dichloro) phenyl ;-S- (3- trifluoromethyl) phenyl

General Step 7 : Ester hydrolysis The products of general step 6 (9Aa, 9Aß, 9Ba, 9Bß, 9Ca, and 9Cß) with their appropriate acyl groups on nitrogen as indicated in the tables above were hydrolysed by treatment of a solution of the ester in tetrahydrofuran/methanol (3: 2, approx 10 mL per gram of substrate) with aqueous sodium hydroxide (1M, 2 equivalents). Removal of the solvents in vacuo yielded the sodium salt of the corresponding acid and sodium hydroxide as crude product (lOAa, 10Aß, 10Ba, 10Bß, 10Ca, and 10ces) with their appropriate acyl groups on nitrogen General Step 8 : Thiol displacement of halide The substrate was dissolved in N, N-dimethylformamide and treated with the appropriate thiol (1.3 equivalents) which was pre-evaporated from 1.3 equivalents of sodium methoxide. 1.3 equivalents of sodium iodide was added to the solution and the mixture stirred overnight at room temperature under nitrogen. After this time, the solvents were removed in vacuo and the crude preparation passed through a plug of silica gel with ethyl acetate eluent, to yield essentially pure product.

Exemplary products are shown in Table 3. M+H ion and relative intensity are shown. Yields, where shown, are purified yields Table 3 MS data/yields for general step 8 of Scheme 2 Substrate 4-methyl 4-methoxy 4-chloro 3,4- 3-tri thiophenol thiophenol thiophenol dichloro fluoromethy thiophenol 1 thiophenol 10AP668 (80) benzoate 10AP 606 (80) acetate 10Aß 744 (100) biphenyl formate lOBa 562 (70) acetate 10Bß 700 (50) biphenyl formate 10Bß 623 (65) benzoate 8Aß 549 (10%) 565 (10%) 569 (15%) 603 (3%) 603 (3%) acetate 53% yield 91% yield 89% yield 64% yield 80% yield 8A 611 (6%) 627 (5%) 631 (8%) 665 (4%) 665 (3%) benzoate 34% yield 29% yield 39% yield 42% yield 40% yield 8AP quant. quant. Yield quant. quant. quant. biphenyl Yield (crude) Yield Yield Yield formate (crude) (crude) (crude) (crude) 8Aß 591 (10%) 607 (10%) 611 (5%) 646 (12%) 645 (15%) "Butyl 67% yield 89% yield 78% yield 89% yield 74% yield formate 8AP 605 (9%) 621 (16%) 625 (3%) 659 (12%) 659 (13%) "Butyl 30% yield 43% yield 77% yield 39% yield 30% yield acetate 8Aa 549 (15%) 565 (10%) 569 (17%) 603 (12%) 603 (7%) acetate 71% yield 96% yield 93% yield 56% yield 86% yield 8Aa 611 (7%) 627 (1%) 631 (2%) 665 (1%) 665 (1%) benzoate 33% yield 28% yield 23% yield 35% yield 26% yield 8Aa Not Not prepared Not Not Not biphenyl prepared prepared prepared prepared formate 8Aa 591 (11%) 607 (17%) 611 (15%) 646 (13%) 645 (27%) "Butyl 45% yield 46% yield 46% yield 47% yield 47% yield formate 8Aa 605 (17%) 621 (26%) 625 (11%) 659 (10%) 659 (21%) "Butyl 20% yield 43% yield 35% yield 41% yield 41% yield acetate Table 3 cont. 8BP 504 (26%) 520 (40%) 524 (30%) 558 (25%) 558 (37%) acetate 74% yield 70% yield 67% yield 81% yield 81% yield 8BP 566 (19%) 582 (7%) 586 (10%) 621 (3%) 620 (10%) benzoate 42% yield 83% yield 73% yield 66% yield 75% yield gap72% yield75% yield37% yield83% yield80% yield biphenyl formate gBp546 (20%) 562 (10%) 566 (10%) 600 (4%) 600 (11%) "Butyl 79% yield 97% yield 97% yield 71% yield 73% yield formate 8BP 560 (14%) 576 (9%) 580 (7%) 614 (3%) 614 (9%) "Butyl 72% yield 68% yield 69% yield 99% yield 75% yield acetate 8Ba acetate 70% yield 50% yield 66% yield 81% yield 59% yield

General Step 9 : Benzylidene cleavage The benzylidene compounds were taken up in methanol and acetonitrile, (100 mg of compound in 1 mL of acetontirile and 2 ml methanol) and treated with amberlite IRA (H+ form) at 45°C for 12 hours. After this time the resin was removed by filtration and the solvents evaporated in vacuo.

The products were purified by reverse phase HPLC with mass

based detection.

Exemplary 1H NMR data: R = acetate: 7.35-8.05, m, 7H (Aromatics); 5.35, d, J=12. 0, 1H (benzylic); 4.95, d, J=12.0,1H (benzylic); 4.55, d, J=8,1H (H-1) ; 3.15-4.05, m, 8H; 1.80, s, 3H (acetate CH3).

R = benzoate: 7.10-8.35, m, 12H (Aromatics); 5.20, d, J=12.0, 1H (benzylic); 5.00, d, J=12.0,1H (benzylic); 4.65, d, J=8,1H (H-1) ; 3.20-4.20, m, 8H.

R = biphenylcarbonyl: 7.10-8.30, m, 16H (Aromatics); 5.25, d, J=12. 0,1H (benzylic); 5.00, d, J=12.0,1H (benzylic); 4.70, d, J=8,1H (H-1) ; 3.20-3.90, m, 8H.

R = tbutylcarbonyl : 7.30-8.10, m, 7H (Aromatics); 5.25, d, J=12.0,1H (benzylic); 5.00, d, J=12. 0,1H (benzylic); 4.65, d, J=8,1H (H-1) ; 3.20-4.15, m, 8H; 0.95, s, 9H (tbutyl 3xCH3).

Exemplary HPLC and mass spectral data products are shown in the attached figures.

Figure 1 LC-MS data for Figure 2 LC-MS data for Figure 3 LC-MS data for

General Step 10 : Coupling of groups to the C-3 acid moiety Acid substrates (10) are dissolved in N, N- dimethylformamide and activated with HBTU in the presence of triethylamine. Peptides with one free amine, amino acids with one free amine or other nucleophillic amines are added in excess and the mixture stirred for 2 hours. After this time the solvents are removed in vacuo and the crude material chromatographed on silica gel to yield the desired product.

In a specific example, substrate 10Aß benzoate was reacted with the tripeptide a-O-benzyl-Y-glutamyl--(2- chlorobenzylcarbamoyl)-lysinyl-O-benzyl-alanine to yield the desired protected product. HPLC and mass spectral data are shown in Figure 4.

In this instance the benzyl and o-chloro-benzyloxycarbonyl protecting groups were removed by hydrogenolysis in methanol with 10% palladium on charcoal as catalyst (1% w/w Pd; 40 psi, 2 hours). The benzylidene was subsequently removed as described in general step 9. In a cognate experiment in which alanine tbutyl ester was used, the tbutyl protecting group and the benzylidene were removed by general step 9. It is expected that BOC amine protecting groups will be similarly amenable to this latter deprotection strategy. ..". I N3 Aco 0 3 OAc < a 9 NH2 OU 14/eneral step5 15a R=H 15b R=MeO O,, N3 p II general step 6 O Nff, Ri (Y""* NH' Ri Or3 16a R=H" 16b R=MeO 17a R=H 17b R=MeO general step 7 p,," N3 general step 10 0 19a R=H OU3 OU3 19a R=H 19b R=MeO 18a R=H 18b R=MeO general step 11 zu 0 Nffkl general step 12 or general step 13 o ? \OX, NH Y Or3 0 0 (Y""'NHILRI 20a R=H 20b R=Me0OR3 21a R=H 21b R=MeO

Scheme 3 17 R3 =-CH2-COOMe 18 R3 =-CH2-COOH 19,20,21 R3 =-CH2-CONH-OBn ;-CH2-CONH-CH (CH3)-COOBn

or 17,18,19,20,21 R3 = is 2-nitrophenyl; benzyl; 4-methylbenzyl; 4-chlorobenzyl; 4-methoxybenzyl; 4- phenylbenzyl; 1-napthylmethyl; 2-napthylmethyl.

R1 is as defined in scheme 1 + Dde; 4-methylphenyl.

Y is shown in the following list:

1-Deoxy-1-azido-3,4,6-tri-O-acetyl-2-deoxy-2-[1-(4, 4- dimethyl-2,6-dioxocyclohex-1-ylidene)-ethylamino]-a-D- glucopyranose (14): 3,4,6-tri-O-Acetyl-2-deoxy-2- [1- (4,4-dimethyl-2,6- dioxocyclohex-1-ylidene)-ethylamino]-a-D-glucopyranosyl bromide (3) (60g, 0.112 mol) is suspended in acetonitrile (280mL) and trimethylsilylazide (TMS-N3) (29.9 RL, 0.224 mol) is added dropwise followed by the dropwise addition of tetrabutylammonium fluoride (1M TBAF in tetrahydrofuran) (225 mL, 0.225 mol). The reaction is stirred for 16 hr protected from light. The solvents are removed under reduced pressure, and the residue is preabsorbed on silica (150g) and the product eluted with ethyl acetate/ petroleum ether (1: 1) (2 L). The solvents are evaporated and the crude residue used directly in the next step.

Alternative preparation of l-Deoxy-l-azido-3, 4,6-tri-O- acetyl-2-deoxy-2- [I- (4, 4-dimethyl-2,6-dioxocyclohex-1- ylidene)-ethylamino]-a-D-glucopyranose (14):

3,4,6-tri-O-Acetyl-2-deoxy-2- [l- (4,4-dimethyl-2,6- dioxocyclohex-l-ylidene)-ethylamino]- (X-D-glucopyranosyl bromide (3) (150g, 0.282 mol) is suspended in ethyl acetate (3000mL) and a solution of 10% aqueous sodium hydrogen carbonate (1500 mL) containing sodium azide (22 g, 0.338 mol) is added. Tetrabutylammonium hydrogen sulfate (28.7g, 30 mol%) was added and the biphasic mixture stirred vigorously for 16h. The organic layer was then separated, extracted and dried, then the solvent removed at reduced pressure. The residue was chromatographed as above to yield the desired product (105g, 75%).

1H NMR (500 MHz, CDC13) 8 13.90 (d, J=9.6,1H), 5.22 (t, J=9. 6,1H), 5.11 (t, J=9. 7,1H), 4.90 (d, J=8.9,1H), 4.36 (dd, J=4.5,12.5,1H), 4.17 (dd, J=12.4,1.7,1H), 3.81- 3.91 (m, 2H), 2.60 (s, 3H), 2.42 (s, 2H), 2.36 (s, 2H), 2.11, (s, 3H), 2.04 (s, 3H), 1.03 (s, 3H) m/z 495 (M+H). l-Deoxy-l-azido-2-deoxy-2-amino-4, 6-benzylidene- (X-D- glucopyranose (15a) : The crude product 14 is taken up in methanol (450 mL) and sodium metal (2.5g, 0.112 mol) added carefully. The reaction vessel is guarded from the light and stirred for 45 minutes. The reaction is neutralized to pH 6 with Amberlite IR 120 (H) resin. The resin is filtered and solvents evaporated under reduced pressure at rt. The residue is adsorbed on silica (150 g) and the product washed out with acetonitrile/water (1: 1) (1L). Solvents are evaporated under reduced pressure (at rt). Remaining water is removed by adding acetonitrile and evaporating under reduced pressure. The crude reaction product is suspended in acetonitrile (dry, 450 mL) and benzaldehyde dimethyl acetale (34.3g, 0.225mol) and para-toluenesulfonic acid monohydrate (0.4g, 0.225mol) were added. The reaction mixture is heated to 80C for 2 hours, then triethylamine (1 equivalent) added and solvents evaporated under reduced pressure. The residue is adsorbed on silica (150g) and the

silica washed with petroleum ether (500 mL). The product is eluted with ethyl acetate/petroleum ether (2/3). After evaporation of the solvents 42,73 g of crude product are obtained (83% yield from the bromo sugar 3). The product is then suspended in MeOH (475mL) and hydrazine hydrate (13.6g, 0.25mol) added at OC. The solution is stirred for 10 minutes and then another 90 minutes at rt. The volume is reduced under vacuum to half, ethyl acetate (200 mL) is added and the organic solution washed with brine. The organic layer is dried on magnesium sulfate and evaporated to dryness. The residue is adsorbed on silica (100 g) and eluted with ethyl acetate/petroleum ether (3/2) (400 mL) then with ethyl acetate (400 mL) and finally with acetonitrile/ethyl acetate (1/5). The product is separated as a white solid (20.31 g, 74%) 1H NMR (500 MHz, CDC13) 8 7.32-7.53 (5H m aromatics), 5.54 (1H, S, Ph-CH) 4.53 (1H, d, J=8. 8, H-1), 4.3-4.4 (lH, m), 3.7-3.8 (1H, m), 3.4-3.6 (3H, m), 2.71 (1H, t, J=9, H-3), 1.62 (2H, br).

Cognate preparation of l-Deoxy-l-azido-2-deoxy-2-amino-4, 6- p-methoxybenzylidene-a-D-glucopyranose (15b) : This compound was prepared in an analogous manner to 15a except that 4-methoxybenzaldehyde dimethyl acetal was used in place of benzaldehyde dimethyl acetal.

1H NMR (500 MHz, CDC13) 8 7.41 (d, J=10,2H), 6.89 (d, J=10, 2H), 5.51 (1H, S) 4.54 (d, J=8.8,1H), 4.35 (dd, J=4.2,10.5,1H), 3.80 (s, 1H), 3.74-3.90 (m, 1H), 3.57- 3.63 (m, 1H), 3.50-3.55 (m, 2H), 2.71 (1H, t, J=9.1,1H. m/z 323.18 (M+H) General step 5 to N-acylate (16a): Example: 1-Deoxy-l-azido-2-deoxy-2-N- (acetyl)-amino-4, 6- benzylidene-a-D-glucopyranose : the product is isolated in 97% yield (2.22g, 6.6 mmol).

1H NMR (500 MHz, CDC13) 627. 26-7.52 (5H, m, aromatics), 5.56 (1H, S, Ph-CH), 4,83 (1H, d, J=9.3), 4.75 (1H, d,

J=4.5), 4.3-4.4 (1H, m), 3.9-4 (lH, m), 3.7-3.8 (1H, m), 3.6- 3.7 (1H, m), 3.5-3.6 (2H, m), 2.0 (3H) General step 5 to N-acylate (16b): Example: l-Deoxy-l-azido-2-deoxy-2-N-(acetyl)-amino-4, 6-p- methoxybenzylidene-a-D-glucopyranose : Was prepared by general method 5 utilising the symmetric anhydride (acetic anhydride).

1H NMR (500 MHz, CDC13) 8 7.41 (d, J=8. 5,2H), 6.90 (d, J=7,2H), 5.51 (1H, S) 5.01 (d, J=9. 5, 1H), 4.36 (dd, J=5, 10.5,1H), 4.18 (t, J=10.0 1H), 3.81 (s, 3H), 3.78 (t, J=10. 0 1H), 3.59 (dd, J=5, 9.5,1H), 3.54 (dd, J=9,19,1H), 3.46 (dd, J=8.5,18,1H), 2.07 (s, 3H). m/z 365.3 (M+H) Example: l-Deoxy-l-azido-2-deoxy-2-N-(benzoyl)-amino-4, 6-p- methoxybenzylidene-a-D-glucopyranose : Was prepared by general method 5 utilising the acid chloride (benzoyl chloride).

M/z 427.3 (M+H) Example: l-Deoxy-l-azido-2-deoxy-2-N-(tbutylcarbonyl)- amino-4,6-p-methoxybenzylidene-a-D-glucopyranose: Was prepared by general method 5 utilising the acid chloride (2,2,2-trimethylacetyl chloride).

M/z 407.4 (M+H) General step 6 to prepare (17a): Example: l-Deoxy-l-azido-2-deoxy-2-N-(acetyl)-amino-4, 6- benzylidene-3- (methyl acetate)- (X-D-glucopyranose : Methyl bromoacetate was employed as the alkylating agent. The target product was isolated in 74% yield (1.97gr). 1H NMR (500 MHz, CDC13) 6S7. 32-7.47 (5H, m, aromatics), 6.73 (1H, d, J=6.6), 5.55 (1H, s), 4.75 (1H, d, J=9.1), 4.3-4.5 (3H, m), 3.6-3.9 (7H, m), 3.5-3.6 (1H, m), 2.1 (3H, s).

General step 6 to prepare (17b):

Example: l-Deoxy-l-azido-2-deoxy-2-N-(acetyl)-amino-4, 6-p- methoxybenzylidene-3-(methyl acetate)-a-D-glucopyranose: Methyl bromoacetate was employed as the alkylating agent.

The target product was isolated in 85% yield.

M/z 437.36 (M+H) Example: 1-Deoxy-l-azido-2-deoxy-2-N- (benzoyl)-amino-4, 6-p- methoxybenzylidene-3- (methyl acetate)-a-D-glucopyranose : Methyl bromoacetate was employed as the alkylating agent.

The target product was isolated in 85% yield.

M/z 499.4 (M+H) Example: 1-Deoxy-l-azido-2-deoxy-2-N- (tbutylacetyl)-amino- 4,6-p-methoxybenzylidene-3-(methyl acetate)-a-D- glucopyranose: Methyl bromoacetate was employed as the alkylating agent. The target product was isolated in 85% yield.

M/z 479.4 (M+H) Example: Preparation of further C-3 alkylated compounds: The appropriate alkyl halide was employed in place of methyl bromoacetate as the alkylating agent. The target product was isolated and yields are shown in parentheses.

Table 4 MS data/yields for general step 6 Scheme 3 compounds 17b

Table of building blocks, MH+ values in ESMS and yields between brackets. R31 Ri-Dde CH3-co 609 68% 547 (40%) 623 (68%) (61%) N02 577 84% 517 (800) 593 (100) Me 591 (541%) 531 (55%) 607 (63%) 6 11 489 551 (89%) 627 (97%) MeO 607 (540%) 547 (80%) 623 (95%) 653 531 593 (78%) 669 (91%) (75%) 627 505 567 (86%) 643 (100%) 627 505 567 (77%) 643 (86%)

General step 10 to prepare (19b): Where R3 is other than- CH2-COOMe, this step is omitted.

Example: The products of hydrolysis of 17b were coupled according to general step 10 with L-alanine-O-benzyl ester to yield compounds of general formula 19b.

N-acetylated compound m/z 584.4 (M+H) N-benzoylated compound m/z 646.5 (M+H)

In a cognate preparation, hydroxylamine-O-benzyl ether was coupled to the products of hydrolysis of 17b.

General step 11: reduction of the azide with Pd/C or with dithiol to prepare (20a and 20b) 1. With Pd/C: starting material (0.74 mmol) is dissolved in dichloromethane (10 mL), catalyst (Pd/C, 150 mg) is added and the solution degassed. The reaction mixture is hydrogenated (H2 at 1 atm) for 1 hour, then filtered and solvent evaporated under reduced pressure. The crude 1- amino glycoside is employed without further purification.

Example. l-Deoxy-l-amino-2-deoxy-2-N-(acetyl)-amino-4,6- benzylidene-3- (methyl acetate)-a-D-glucopyranose : product was isolated in quantitative yield. 1H NMR (500 MHz, CDC13) 627. 33-7.50 (5H, m, aromatics), 5. 56 (1H, s), 4.47-4.55 (1H, m), 4.27-4.46 (2H, m), 4.15 (1H, d, J=9), 3.60-3.83 (7H, m), 3.37-3.44 (1H, m), 2.08 (3H, s).

2. With dithiol: starting material (0.12 mmol) is dissolved in chloroform/methanol (1/1) (1.2 mL), dithiotreitol (57 mg, 3 equiv) is added and the solution degassed using a nitrogen stream. The reaction mixture is stirred under nitrogen for 10 hours. The reaction mixture is dilited with chloroform washed with water and brine, dried with magnesium sulfate and solvent evaporated. The crude 1- amino glycoside is employed without further purification for the generation for the isocyanate.

General step 12: formation of a urea bond 21a and 21b The Y substituents are introduced by reacting of in situ generated isocyanate (from the 1-aminopyranose 20a or 20b) with the amino functionality of the Y group.

The 1-isocyanato pyranose is first generated by treating the 1-aminopyranose 20 with one equivalent of one of the following reagents: phosgene, triphosgene, 1,1'- carbonyldiimidazole, or N, N'-disuccinimidyl carbonate.

Suitable solvents for this purpose are dichloromethane,

dimethylformamide or chloroform. The Y group is then added directly (1 equivalent) to the crude isocyanate mixture and the reaction is left stirring for 16 hours. 1 equivalent of diisopropylethylamine is added if the reaction is not complete after this time. The reaction is worked up by evaporating the solvents, adding dichloromethane and filtering the precipitated product.

The Y groups are prepared using commonly used amide bond forming procedures or urea bond forming procedures from commercially available precursors. Examples of suitable amide bond forming reagents include HBTU, BOP, HATU, and PyBOP. The urea bond in some of the Y groups are generated through the reaction of an isocyanate and an amine using well known procedures. The isocyanates are generated as above for the sugar isocyanate.

Y group reagents for general step 12 are in table 5: Table 5 Where Y = benzylamine m/z 514.52 M+H RT 8.55 minutes 1H nmr: (CDC12) 1.83 (s, 3H) 3.45 (s, 3H) 3.30-4.30 (m 10H) 4.92 (dd, J=lOHz, lHz, 1H) 5.60 (s, 1H), 6.45 (d J=lOHz, 1H), 6.85 (t, J=6 Hz, 1H) 7.20-7.45 (m 10H), 8.20 (d J=9 Hz, 1H).

General step 13 : formation of an amide bond 21a and 21b The Y substituents are introduced through an amide bond forming reaction between the 1-amino pyranose 20 and

the carboxylic acid functionality on the Y group. The amine (20) (0.2 mmol) is suspended in anhydrous DMF (1.2 mL) and a solution of the appropriate acid (0.95 equiv), HBTU (87 mg, 1.15 equiv), diisopropylamine (62 mg, 83 ZL, 2.4 equiv) in DMF (0.8 mL) was added. The mixture was stirred for 16 hours and the solution then diluted with chloroform (10 mL), extracted with 10% citric acid solution, dried and solvents removed to yield the desired amides (21) in yields varying from 40% to 90%.

Y group reagents (carboxylic acids) for general step 13 are shown in table 6:

Table 6 0 general step 14 general step 11 OH NHRI OR3 NHKR, OH OR3 16a R=H 16b R=MeO 22a R=H 22bR=MeO general step 11 0) 0 general step 12 O NH Y or general step 13 ot0sf"NH2 i 1T 1* o t ! ! o OR3 24a R=H 24b R=MeO 23a R=H 23bR=MeO

Scheme 4 R1 is as defined in scheme 3 R3 is acetyl; 4-chlorobenzoyl Y is as defined in scheme 3 Acyl protection of compounds 16a and 16b to form 22a and 22b. General step 14 Compound 16 (0.27 mmol) was dissolved in DMF (1.4 ml) and diisopropylethylamine (71 mg, 96 F1, 2 equiv) added.

Acetic anhydride (56 mg, 52 F1, 2 equiv) was added followed by a catalytic amount of DMAP. The mixture was stirred for 16 h, water added and stirring continued for a further 30 min. The mixture was diluted with chloroform, washed with 10% citric acid, NaHCO3 solution, brine, dried (MgSO4) and evaporated to give the desired compound as a white solid (85-95%).

In a cognate preparation 4-chlorobenzoyl chloride was used in place of acetic anhydride.

Example: 1-Deoxy-l-azido-2-deoxy-2-N- (acetyl)-amino-3-p- chlorobenzoyl-4,6-p-methoxybenzylidene-a-D-glucopyranose 1H nmr (d6-DMSO, 500 MHz) 1.91 (s, 3 H), 3.71 (dt, J = 7, 10 Hz, 1 H), 3.76 (s, 3 H), 3.84 (t, J = 10 Hz, 1 H), 3.92 (t, J = 9.5 Hz, 1 H), 4.12

(dd, J = 9.5,19 Hz, 1 H), 4.30 (dd, J = 9. 5,10 Hz, 1 H), 5.07 (d, J = 9.5 Hz, 1 H), 5.32 (t, J = 10 Hz, 1 H), 5.63 (s, 1 H), 6.93 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.5 Hz, 2 H), 7.59 (d, J = 8.5 Hz, 2 H), 7.78 (d, J = 8.5 Hz, 2 H), 8.73 (d, J = 9 Hz, 1 H) Compounds of the type 21a, 21b, 24a and 24b were further elaborated by deprotection of ester groups as exemplified by general procedure 7 followed by cleavage of the benzylidene protecting groups according to general procedure 9 to yield the final compounds as exemplified by table 7.

Compounds were analysed by HPLC/MS with evaporative light scattering detection. Retention times and peak purities for the peaks corresponding to the desired compound as detected by mass spectrometry are shown. NA denotes prepared but not analysed. Codes for Y are as shown in table 6 above.

Table 7 Number Y R1 R3 Retention Time Purity % ELS (area) 1 B Me CH2CO2Me 1. 82 77. 7 2 H Me CH2CO2Me 2. 9 78. 3 3 G Me CH2CO2Me 3. 4 51. 2 4 B Phe CH2CO2Me 3. 35 49. 1 5 B tBu CH2CO2Me 3. 28 15. 9 6 B Me H 1. 25 66. 0 7 H Me H 2. 73 99. 3 8 A tBu H 3. 51 82. 1 9 H tBu H 3. 38 85. 0 10 G tBu H 3. 75 86. 4 11 H Me CH2C02H 2. 92 80. 9 12 G Me CH2CO2H 3.43 83. 0 13 A Phe CH2CO2H 3.69 70. 5 14 H Phe CH2CO2H 3. 6 88. 9 15 A Me CH2C02H 3. 06 87. 9 16 C Me CH2CO2Me 2. 51 86. 9 17 F Me CH2CO2Me 2.65 86. 5 18 J Me CH2CO2Me 1.36 53. 7 19 D Me CH2CO2Me 2.57 83. 2 20 C Phe CH2CO2Me 3.46 92. 9 21 F Phe CH2CO2Me 3.45 51. 8 22 F Phe CH2CO2Me 3.69 45. 1 23 J Phe CH2CO2Me 2.99 69. 1 24 D Phe CH2CO2Me 3.41 73. 6 25 C tBu CH2CO2Me 3.4 58. 3 26 F tBu CH2CO2Me 3.38 55. 5 27 J tBu CH2CO2Me 2.96 29. 5 28 D tBu CH2CO2Me 3.35 62. 3 29 E Me CH2CO2Me 2.18 81. 5 30 E Phe CH2CO2Me 3.43 89. 2 31 E tBu CH2CO2Me 3.34 23. 4 32 C Me H 1. 88 95. 2 33 F Me H 2. 19 95. 1 34 D Me H 2. 03 73. 1 35 F Phe H 4. 2 0. 5 36 C tBu H 3. 23 89. 0 37 F tBu H 3. 26 86. 1 38 J tBu H 2. 64 85. 3 39 D tBu H 3. 2 88. 2 40 E Me H 1. 5 95. 0 41 E tBu H 3. 17 90. 5 42 B Me CH2CO2H 2.5 84. 9 43 J Me CH2C02H 0. 91 72. 3 44 D Me CH2CO2H 2.57 82. 8 45 C Phe CH2CO2H 3.48 87. 1 46 F CH2CO2H 3. 51 97. 7 47 J Phe CH2CO2H 2.87 74. 4 48 D Phe CH2CO2H 3.44 89. 2 49 C tBu CH2C02H 3. 41 96. 0 50 F tBu CH2CO2H 3.4 96. 3 51 J tBu CH2CO2H 2.83 38. 1 52 D tBu CH2C02H 3. 37 95. 6 53 E Me CH2CO2H 2.22 83. 0 54 E Phe CH2CO2H 3.43 83. 1 55 K Me CH2CO2Me 2.88 33. 2 56 L Me CH2CO2Me 3.07 37. 1 57 N Me CH2CO2Me 3.16 54. 0 58 0 Me CH2C02Me 3. 26 66. 2 59 P Me CH2CO2Me 3.26 61. 4 60 I Me CH2CO2Me 2.74 55. 9 61 Q Me CH2CO2Me 3.3 46. 5 62 K Phe CH2CO2Me 3.61 90. 4 63 O Phe CH2CO2Me 3.81 86. 8 64 I Phe CH2CO2Me 3.52 87. 1 65 A Me CH2CONHCH (CH3) CO2Bn 4.09 85. 8 66 C Me CH2CONHCH (CH3) C02Bn 3. 93 88. 6 67 D Me CH2CONHCH (CH3) CO2Bn 3.95 89. 1 68 F Me CH2CONHCH (CH3) CO2BN 3.89 86. 0 69 G Me CH2CONHCH (CH3) CO2Bn 4.38 85. 4 70 K Me CH2CONHCH (CH3) CO2BN 3.93 86. 3 71 I Me CH2CONHCH (CH3) CO2Bn 3.98 80. 2 72 Q Me CH2CONHCH (CH3) CO2BN 3.93 86. 2 73 Q Phe CH2CO2Me 3.92 98. 5 74 A pMePhe H 4. 00 30. 7 75 C pMePhe H 3. 77 54. 5 76 F pMePhe H 3. 75 64. 0 77 K pMePhe H 3. 91 84. 5 78 M pMePhe H 4. 85 2. 1 79 L Me CH2CO2H 3.07 92. 5 80 N Me CH2CO2H 3.15 59. 9 81 0 Me CH2C02H 3. 26 72. 4 82 P Me CH2CO2H 3.25 69. 4 83 I Me CH2CO2H 2.75 50. 4 84 Q Me CH2CO2H 3.32 54. 7 85 R Me CH2C02H 4. 32 79. 2 86 K Phe CH2C02H 3. 61 80. 7 87 I PhE CH2CO2H 3.53 88. 2 88 A Me CH2CONHCH (CH3) CO2H 2.66 18. 5 89 C Me CH2CONHCH (CH3) CO2H 2.87 69. 4 90 D Me CH2CONHCH (CH3) CO2H 2.60 1. 7 91 G Me CH2CONHCH (CH3) CO2H 3.50 51. 8 92 H Me CH2CONHCH (CH3) CO2H 3.07 81. 0 93 L Me CH2CONHCH (CH3) C02H 3. 17 52. 5 94 M Me CH2CONHCH (CH3) CO2H 3.34 83. 7 95 I Me CH2CONHCH (CH3) CO2H 2.97 64. 3 96 Q Me CH2CONHCH (CH3) CO2H 3.38 24. 4 97 C Phe CH2CONHCH (CH3) C02Bn 4. 58 93. 0 98 E Phe CH2CONHCH (CH3) CO2Bn 4.53 87. 1 99 F Phe CH2CONHCH (CH3) CO2Bn 4.49 91. 8 100 G Phe CH2CONHCH (CH3) CO2Bn 5.66 74. 6 101 H Phe CH2CONHCH (CH3) CO2Bn 4.71 87. 2 102 J Phe CH2CONHCH (CH3) CO2Bn 3.85 95. 2 103 K Phe CH2CONHCH (CH3) CO2Bn 4.65 & 4. 78 74. 4 104 N Phe CH2CONHCH (CH3) CO2Bn 5.25 87. 5 105 P Phe CH2CONHCH (CH3) CO2Bn 5.35 55. 8 106 I Phe CH2CONHCH (CH3) C02Bn 4. 67 26. 4 107 Q Phe CH2CONHCH (CH3) CO2Bn 5.64 81. 7 108 B Me CH2CONHOBn 1. 82 26. 5 109 C Me CH2CONHOBn 2.55 39. 1 110 D Me CH2CONHOBn 2.58 35. 1 111 E Me CH2CONHOBn 2.22 16. 5 112 F Me CH2CONHOBn 2. 67 35. 9 113 G Me CH2CONHOBn 3. 98 50. 6 114 H Me CH2CONHOBn 2. 92 29. 4 115 J Me CH2CONHOBn 3.01 25. 7 116 N Me CH2CONHOBn 3. 83 72. 5 117 A Phe CH2CONHOBn 3. 70 66. 2 118 C Phe CH2CONHBn 3.50 44. 1 119 D Phe CH2CONHOBn 4. 01 50. 8 120 F Phe CH2CONHOBn 4. 05 56. 9 121 G Phe CH2CONHOBn 3. 92 80. 1 122 H Phe CH2CONHOBn 3. 57 77. 3 123 K Phe CH2CONHOBn 3. 60 48. 4 124 L Phe CH2CONHBn 3.71 72. 5 125 P Phe CH2CONHOBn 3. 84 77. 4 126 Q Phe CH2CONHOBn 3. 91 57. 8 127 A Phe CH2CONHCH (CH3) C02H 3. 72 36. 6 128 E Phe CH2CONHCH (CH3) CO2H 3.47 87. 2 129 F Phe CH2CONHCH (CH3) CO2H 3.48 92. 4 130 G Phe CH2CONHCH (CH3) CO2H 0.00 0. 0 131 H Phe CH2CONHCH (CH3) CO2H 3.61 92. 1 132 J Phe CH2CONHCH (CH3) CO2H 2.90 91. 4 4.65 & 133 K Phe CH2CONHCH (CH3) CO2H 4.80 74. 7 134 L Phe CH2CONHCH (CH3) CO2H 3.70 93. 9 135 N Phe CH2CONHCH (CH3) CO2H 3.77 94. 8 136 P Phe CH2CONHCH (CH3) CO2H 3.84 87. 3 137 I Phe CH2CONHCH (CH3) CO2H 3.53 55. 0 138 B tBu CH2CO2H NA NA 139 A tBu CH2C02H NA NA 140 H tBu CH2C02H NA NA 141 F CH3 CH2CO2H NA NA 142 M CH3 CH2CO2Me NA NA 143 R CH3 CH2CO2Me NA NA 144 H CH3 CH2CONHCH (CH3) CO2Bn NA NA 145 L CH3 CH2CONHCH (CH3) CO2Bn NA NA 146 P CH3 CH2CONHCH (CH3) CO2Bn NA NA 147 J pC1 Phe H NA NA 148 R pClPhe H NA NA 149 D pMePhe H NA NA 150 H pMePhe H NA NA 151 P pMePhe H NA NA 152 I pMePhe H NA NA 153 Q pMePhe H NA NA 154 K CH3 CH2CO2H NA NA 155 M CH3 CH2CO2H NA NA 156 L Phe CH2CONHCH (CH3) CO2Bn NA NA 157 M Phe CH2CONHCH (CH3) CO2Bn NA NA 158 B Phe H NA NA 159 H Phe H NA NA 160 G Phe H NA NA 161 C Phe H NA NA 162 E Phe H NA NA 163 D Phe H NA NA 164 A Phe H NA NA 165 B Phe H NA NA 166 H Phe H NA NA 167 G Phe H NA NA 168 C Phe H NA NA 169 E Phe H NA NA 170 D Phe H NA NA 171 A Phe H NA NA 172 K pClPhe H NA NA 173 O pClPhe H NA NA 174 I pClPhe H NA NA 175 B pClPhe H NA NA 176 H pClPhe H NA NA 177 G pClPhe H NA NA 178 C pClPhe H NA NA 179 F pClPhe H NA NA 180 E pClPhe H NA NA 181 D pClPhe H NA NA 182 A pClPhe H NA NA 183 K pClPhe H NA NA 184 O pClPhe H NA NA 185 I pClPhe H NA NA 186 B pClPhe H NA NA 187 H pClPhe H NA NA 188 G pClPhe H NA NA 189 C pC1Phe H NA NA 190 F pClPhe H NA NA 191 E pClPhe H NA NA 192 D pClPhe H NA NA 193 A pClPhe H NA NA 194 L pMePhe H NA NA 195 O pMePhe H NA NA 196 R pMePhe H NA NA 197 B pMePhe H NA NA 198 G pMePhe H NA NA 199 E pMePhe H NA NA 200 L pMePhe H NA NA 201 0 pMePhe H NA NA 202 R pMePhe H NA NA 203 B pMePhe H NA NA 204 G pMePhe H NA NA 205 E pMePhe H NA NA Preparation of sulfonamide derivative 25.

figure 5 Compound 19a (40 mg) in which R1 is methyl and R3 is- CH2COOMe was dissolved in dichloromethane (1 mL), to which was added triethylamine (13 mg, 1.2 equiv) followed by p- toluenesulfonyl chloride (24 mg, 1.2 equiv). The reaction was stirred at room temperature for 18 hours, diluted with dichloromethane and extracted with 10% citric acid, saturated sodium hydrogen carbonate and brine, dried over magnesium sulfate and the solvents removed in vacuo to yield 25 (figure 5) (33 mg, 59 %).

Solid phase approach: The groups may be attached to a solid support via an ester linking bond (R6 or Rg= resin-CH2-CO-). These resin

bound groups are prepared by linking alpha amino, alpha- hydroxy, or alphathiohydroxy acids to a commercially available hydroxy or chloromethylated resin. Suitable examples include but are not limiteds to tentagel-OH, hydroxymethyl polystyrene, Novasyn TG-hydroxy resin, or chloromethylated polystyrene.

Exemplary compounds were synthesized on solid support as described by the following reaction scheme 5: Fmoc-NH NH, 3'Boc COZH NH 'NH CO2H \ M3'Boc + step I C=O Resin OH Resin 1 Nu NH Fmoc- Fmoc-NH. NH NH-Phe r l's 31 C=O step 3 Step 2 C=O O Resin SP2 Resin-O f Resin O 12 0 0 NH NH-* NH NH-Phe 7tTp-4'0'y 3 y O C=O O \ () \ i'V 0 Resin /OH ft \ zu o 0 step 5 0-0 NH. NH. NH NH-Phe 3 0 C02H 0 0'Y'NHbCH3 OH ll If O Scheme 5 Example solid phase strategy Solid Phase Step 1 : Attachment to hydroxy-resin Novasyn TG-hydroxy resin (purchased from Novabiochem) (1 g, 0.37 mmol/gr) is mixed with DMF (6mL), left standing for 30 min. and then filtered off. Fmoc-L-Lysine (Boc)-OH (940 mg, 2 mmol) is dissolved in dichloromethane (4 mL) at OC and dicyclohexylcarbodiimide (206 mg, lmmol) is added at once. After 20 minutes the DCM is evaporated, DMF (3 mL)

added and the solution is added to the filtered resin.

Dimethylaminopyridine (5 mg, 0.04 mmol) is added to the mixture and the reaction is left for 60 minutes. The resin is filtered and washed with DMF (3 x 6 mL), MeOH/DCM (1: 1) (3 x 6mL), and finally DCM (3 x 6 mL). The resin is further dried by air.

Solid Phase Step 2 : Removal of the Boc group The resin (1.1 g) is treated with a solution of trifluoroacetic acid (3 mL) in DCM (3mL) for 2 minutes.

The resin is then filtered and washed with DCM (5x 6mL).

Solid Phase Step 3 DCM (6mL) is added to the resin (1.1 g) followed by . diisopropylethylamine (0.65 mL, 3.7 mmol) and triphosgene (90 mg, 0.25 mmol). After 10 minutes the solvent is filtered and the resin washed with DCM (3 x 6 mL). Aniline (186 mg, 2 mmol) is dissolved in DCM (4 mL) and the solution added to the resin. After 30 minutes the resin is filtered, washed with DCM (4x 4mL) and air dried.

Solid Phase Step 4 The resin (1.1 g) is treated with piperidine/DMF (1: 1) (5 mL) for 5 minutes. The resin is filtered and washed with DMF (3 x 6 mL), MeOH/DCM (1: 1) (3 x 6mL), and finally DCM (3 x 6mL). DCM (6mL) is added to the resin followed by diisopropylethylamine (0.65 mL, 3.7 mmol) and triphosgene (90 mg, 0.25 mmol). After 10 minutes the solvent is filtered and the resin washed with DCM (3 x 6 mL). 4,6-Benzylidene-2-deoxy-2-N-acetamido-l-deoxy-l-amino- alpha-D-muramic acid (155 mg, 0.4 mmol) is dissolved in DMF (4 mL) and the solution added to the resin. After 12 hours the resin is filtered and washed with DMF (3 x 6 mL), MeOH/DCM (1: 1) (3 x 6mL), and finally DCM (3 x 6 mL). The resin is further dried by air.

solid Phase Step 5 A solution of aqueous NaOH (1M, 0.2 mL) and MeOH (2mL) is added to the resin and the reaction left for 40 min. The resin is filtered and washed with MeOH (3 x 6mL).

The filtrates are combined, neutralized with 0. 1M HC1 and solvent evaporated.

The target product was detected by LCMS at m/z 658 (M+H), Molecular Weight calc. For C3lH39N5011 : 657 g/mol.

It will be apparent to the person skilled in the art that while the invention has been described in some detail for the purposes of clarity and understanding, various modifications and alterations to the embodiments and methods described herein may be made without departing from the scope of the inventive concept disclosed in this specification.

References cited herein are listed on the following pages, and are incorporated herein by this reference.

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